Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

ATP-sensitive potassium (K(ATP)) channels regulate insulin release, vascular tone, and neuronal excitability. Whether these channels are modulated by NO, a membrane-permeant messenger in various physiological and pathological processes, is not known. The possibility of NO signaling via K(ATP) channel modulation is of interest because both NO and K(ATP) have been implicated in physiological functions such as vasodilation and neuroprotection. In this report, we demonstrate a mechanism that leads to K(ATP) activation via NO/Ras/mitogen-activated protein kinase pathway. By monitoring K(ATP) single-channel activities from human embryonic kidney 293 cell-attached patches expressing sulfonylurea receptor 2B and Kir6.2, we found K(ATP) stimulation by NO donor Noc-18, a specific NO effect abolished by NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO) but not guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). NO stimulation of K(ATP) is indirect and requires Ras and mitogen-activated protein kinase kinase activities. Blockade of Ras activation by pharmacological means or by coexpressing either a dominant-negative or an S-nitrosylation-site mutant Ras protein significantly abrogates the effects of NO. Inhibition of mitogen-activated protein kinase kinase abolishes the NO activation of K(ATP) but suppression of phosphatidylinositol 3-kinase does not. The NO precursor l-Arg also stimulates K(ATP) via endogenous NO synthase and the Ras signaling pathway. In addition, in rat hippocampal neurons, the protective effect of ischemic preconditioning induced by oxygen-glucose deprivation requires K(ATP) and NO synthase activity during preconditioning. Thus, neuroprotection caused by NO released during the short episode of sublethal ischemia may be mediated partly by K(ATP) stimulation.
 ...
PMID:NO stimulation of ATP-sensitive potassium channels: Involvement of Ras/mitogen-activated protein kinase pathway and contribution to neuroprotection. 1513 49

Adenosine triphosphate-sensitive potassium (K(ATP)) channels are thought to mediate the stress response by sensing intracellular ATP concentration. Cardiomyocyte K(ATP) channels are composed of the pore-forming Kir6.2 subunit and the regulatory sulfonylurea receptor 2 (SUR2). We studied the response to acute isoproterenol in SUR2 null mice as a model of acute adrenergic stress and found that the episodic coronary vasospasm observed at baseline in SUR2 null mice was alleviated. Similar results were observed following administration of a nitric oxide donor consistent with a vasodilatory role. Langendorff-perfused hearts were subjected to global ischemia, and hearts from SUR2 null mice exhibited significantly reduced infarct size (54+/-4 versus 30+/-3%) and improved cardiac function compared to control mice. SUR2 null mice have hypertension and develop cardiac hypertrophy. However, despite longstanding hypertension, fibrosis was absent in SUR2 null mice. SUR2 null mice were administered nifedipine to block baseline coronary vasospasm, and hearts from nifedipine-treated SUR2 null mice exhibited increased infarct size compared to untreated SUR2 null mice (42+/-3% versus 54+/-3%). We conclude that conventional sarcolemmal cardiomyocyte K(ATP) channels containing full-length SUR2 are not required for mediating the response to acute cardiovascular stress.
 ...
PMID:Mice lacking sulfonylurea receptor 2 (SUR2) ATP-sensitive potassium channels are resistant to acute cardiovascular stress. 1776 61

The adult myocardium relies on oxidative metabolism. In ischemic myocardium, such as the embryonic heart, glycolysis contributes more prominently as a fuel source. The sulfonylurea receptor 2 (SUR2) was previously implicated in the normal myocardial transition from glycolytic to oxidative metabolism that occurs during adaptation to postnatal life. This receptor was now selectively deleted in adult mouse myocardium resulting in protection from ischemia reperfusion injury. SUR2-deleted cardiomyocytes had enhanced glucose uptake, and SUR2 forms a complex with the major glucose transporter. These data identify the SUR2 receptor as a target to shift cardiac metabolism to protect against myocardial injury.
 ...
PMID:Deletion of Sulfonylurea Receptor 2 in the Adult Myocardium Enhances Cardiac Glucose Uptake and Is Cardioprotective. 3106 27